Improving the delivery of drugs and other agents to target cells and tissues has been the focus of considerable research for many years. Though many attempts have been made to develop effective methods for importing biologically active molecules into cells, both in vivo and in vitro, none has proved to be entirely satisfactory. Optimizing the association of the inhibitory drug with its intracellular target, while minimizing intercellular redistribution of the drug, e.g., to neighboring cells, is often difficult or inefficient.
Most agents currently administered to a patient parenterally are not targeted, resulting in systemic delivery of the agent to cells and tissues of the body where it is unnecessary, and often undesirable. This may result in adverse drug side effects, and often limits the dose of a drug (e.g., glucocorticoids and other anti-inflammatory drugs) that can be administered. By comparison, although oral administration of drugs is generally recognized as a convenient and economical method of administration, oral administration can result in either (a) uptake of the drug through the cellular and tissue barriers, e.g., blood/brain, epithelial, cell membrane, resulting in undesirable systemic distribution, or (b) temporary residence of the drug within the gastrointestinal tract. Accordingly, a major goal has been to develop methods for specifically targeting agents to cells and tissues. Benefits of such treatment includes avoiding the general physiological effects of inappropriate delivery of such agents to other cells and tissues, such as uninfected cells.
Intracellular pathogens are the etiologic agents of a number of human disease states, e.g., infections caused by Mycoplasma pneumoniae and Chlamydia trachomatis, coronary-artery disease associated with Chlamydia pneumoniae infection, tuberculosis, acquired immune deficiency syndrome (AIDS) and pneumonia, often associated with Mycobacterium avium-intracellulare complex (MAC).
Numerous compounds have been shown to be effective as anti-infective compounds. For example, Cefixime (U.S. Pat. No. 5,252,731) is an orally active third generation cephalosporin with in vitro antibacterial activity against most important lower respiratory pathogens. Cefixime is active against Haemophilus influenzae, Moraxella catarrhalis and penicillin-susceptible Streptococcus pneumoniae but not Staphylococcus aureus. Cefixime is an effective treatment for mild to moderate lower respiratory tract infections (Drugs, 1995, 49(6), 1007). It is also one of the best choices for uncomplicated gonococcal infections (Clin Infect Dis., 1995, 20 Suppl 1, S47). As with certain other drugs of its class, gastrointestinal disturbances are the most frequently reported adverse events in patients taking cefixime, and cases of pseudomembranous colitis have been reported (Drugs, 1995, 49(6), 1007).
Erythromycin has enjoyed over 40 years of use as an agent primarily for the treatment of infections caused by gram-positive bacteria. Its semi-synthetic derivatives clarithromycin and azithromycin have seen use for empiric treatment of respiratory tract infections caused by both gram-positive organisms and some gram-negative organisms such as Haemophilus influenzae and Moraxella catarrhalis (see The Sanford Guide to Antimicrobial Therapy,” 2002, 32nd Edition, David N. Gilbert, MD, Robert C. Moellering, Jr. MD, Merle A. Sande, MD, Eds., Antimicrobial Therapy, Inc., Hyde Park, Vt., also EP 0041355, U.S. Pat. Nos. 4,328,334 and 4,331,803). The antibiotics of this family are also particularly useful at treating so-called “atypical” organisms such as Chlamydia pneumoniae, Chlamydia trachomatis, and Mycoplasma pneumoniae, among others.
Chlamydia pneumonia has recently been cited as a potential contributor to heart/coronary artery disease and there have been reports that antibiotics that clear infection by chlamydia may have value in treating or preventing heart or coronary artery disease (see U.S. Pat. No. 6,281,199 and references cited therein). Since Chlamydia pneumonia is an intracellular pathogen, a semi-synthetic erythromycin antibiotic designed to accumulate in the intracellular space may be superior to older erythromycins at treatment of infection by intracellular bacteria. The same may be a useful agent for the treatment and prevention of heart and coronary artery disease.
Mycobacterium tuberculosis, the causative agent of tuberculosis, is an intracellular organism. Drugs used in the treatment of tuberculosis accumulate inside infected cells at sufficient concentration in order to successfully eradicate the infection. Ethambutol is currently employed in the combination therapy of active tuberculosis infection, as well as in a number of other indications including treatment of mycobacterial illnesses, including pulmonary and extra-pulmonary tuberculosis (see “The Sanford Guide to Antimicrobial Therapy,” 2002, 32nd Edition, David N. Gilbert, MD, Robert C. Moellering, Jr. MD, Merle A. Sande, MD, Eds., Antimicrobial Therapy, Inc., Hyde Park, Vt.). As with other anti-mycobacterial drugs, there are significant toxicities associated with ethambutol use (see “Martindale—The Complete Drug Reference—Monographs”, 2002-3003, The Pharmaceutical Press). An ethambutol derivative designed to concentrate in the intracellular space, which is the site of infection, may be of particular importance since such a derivative may be effective at treating or preventing mycobacterial illness at a lower dose than that which is currently used for ethambutol itself. Furthermore, such a derivative that concentrates within the cell may have pharmacodynamic properties that allow it to overcome strains that have developed resistance to standard-dose ethambutol treatment protocols.
Drugs such as isoniazid (INH) accumulate inside infected cells at sufficient concentration in order to effectively treat infections caused by Mycobacterium tuberculosis. INH is currently an agent of choice for the mono-therapy prophylaxis of tuberculosis and an agent of choice used in combination for the treatment of active tuberculosis infection (see “The Sanford Guide to Antimicrobial Therapy,” 2002, 32nd Edition, David N. Gilbert, MD, Robert C. Moellering, Jr. MD, Merle A. Sande, MD, Eds. Antimicrobial Therapy, Inc. Hyde Park, Vt.). The hepatotoxicity of INH is known to increase with the age of the patient. In particular, patients over 35 years of age are thought to be at significant risk of liver damage associated with INH use (see “Martindale—The Complete Drug Reference—Monographs”, 2002-3003, The Pharmaceutical Press).
Pyrazinamid (PZA, U.S. Pat. No. 2,149,279) is currently employed in the combination therapy of active tuberculosis infection (see “The Sanford Guide to Antimicrobial Therapy,” 2002, 32nd Edition, David N. Gilbert, MD, Robert C. Moellering, Jr. MD, Merle A. Sande, MD, Eds., Antimicrobial Therapy, Inc., Hyde Park, Vt.). As with other anti-mycobacterial drugs there are significant toxicities associated with PZA use (see “Martindale—The Complete Drug Reference—Monographs”, 2002-3003, The Pharmaceutical Press).
Rifabutin (RBT, EP 0,552,018 and U.S. Pat. No. 4,086,225) is currently employed in the combination therapy of active tuberculosis infection and has proven of particular value since 30% of strains resistant to rifampicin (an older semi-synthetic antibiotic also of the rifamycin family) remain sensitive to rifabutin (see “The Sanford Guide to Antimicrobial Therapy,” 2002, 32nd Edition, David N. Gilbert, MD, Robert C. Moellering, Jr. MD, Merle A. Sande, MD, Eds., Antimicrobial Therapy, Inc., Hyde Park, Vt.). Rifabutin is also used in the treatment and/or prevention of other mycobacterial illness such as the Mycobacterium avium-intracellulare complex (MAC) associated with AIDS. Additionally, RBT was investigated in the potential chemotherapy of AIDS since it has been shown to be a reverse transcriptase inhibitor (see Pharm. Pharmacol. Lett. 1993, 3, 1) and to inhibit the growth of HIV in vitro (see Antimicrob. Agents Chemother. 1988, 32, 684). However, clinical efficacy against AIDS or HIV has not been demonstrated.
As with other anti-mycobacterial drugs there are side effects associated with RBT use (see any recent issue of “The Physicians Desk Reference”). An RBT derivative designed to concentrate in the intracellular space, which is the site of infection, may be of particular importance since such a derivative may be effective at treating or preventing mycobacterial illness at a lower dose than that which is currently used for RBT itself and is associated with toxicity. Furthermore, such a derivative that concentrates within the cell may have pharmacodynamic properties that allow it to overcome strains that have developed resistance to standard-dose RBT treatment protocols. Additionally, an RBT analog that is designed to accumulate within the cells of the immune system may have value in the treatment of HIV infection and AIDS, while RBT itself and older rifamycins so far have not shown promise in the antiviral chemotherapy of HIV.
Rifampicin (RIF, U.S. Pat. No. 3,342,810) is currently employed in the combination therapy of active tuberculosis infection (see “The Sanford Guide to Antimicrobial Therapy,” 2002, 32nd Edition, David N. Gilbert, MD, Robert C. Moellering, Jr. MD, Merle A. Sande, MD, Eds., Antimicrobial Therapy, Inc., Hyde Park, Vt.). RIF also has value in the treatment and prevention of other mycobacterial and bacterial illness. Other rifamycins such as rifabutin have been shown to be reverse transcriptase inhibitors (Pharm. Pharmacol. Lett. 1993, 3, 1) and to have activity against the human immunodeficiency virus in vitro (Antimicrob. Agents Chemother. 1988, 32, 684). For this reason, rifampicin derivatives also may have value in the treatment of HIV.
Fluoroquinolones are a broad-spectrum class of synthetic antibacterial agents and have the rare quality of being among the only common classes of broad-spectrum antibacterial drug, members of which have shown therapeutically significant antimicrobial activity against Mycobacterium tuberculosis. Ciprofloxacin (see U.S. Pat. No. 4,670,444), levofloxacin, and sparfloxacin, while not approved by the FDA for use in the treatment of tuberculosis, have been added to combination regimens for anti-tuberculosis therapy (see The Sanford Guide to Antimicrobial Therapy,” 2002, 32nd Edition, David N. Gilbert, MD, Robert C. Moellering, Jr. MD, Merle A. Sande, MD, Eds., Antimicrobial Therapy, Inc., Hyde Park, Vt.).
Thus, there is a need for therapeutic anti-infective agents with improved pharmacological properties, e.g., drugs having improved anti-infective activity and pharmacokinetic properties, including improved oral bioavailability, greater potency and extended effective half-life in vivo.
New anti-infective compounds should have fewer side effects, less complicated dosing schedules, and be orally active. In particular, there is a need for a less onerous dosage regimen, such as one pill, once per day.
Assay methods capable of determining the presence, absence or amounts of infection inhibition are of practical utility in the search for anti-infectives as well as for diagnosing the presence of conditions associated infection.